Cancer is one of the most dreaded diseases of mankind, it is a leading cause of death throughout the world, currently, one in 4 deaths in the United States is due to cancer [1]. More than ten million new cancer cases occur annually, roughly half of which is in the developed countries, and the disease causes over six million deaths a year [2,3]. Recent studies revealed that cancer has become an ever-increasing problem in Saudi Arabia [4-6]. In 2005, cancer killed approximately 12,000 of Saudi people, 8000 of those people were under age of 70 [7]. Furthermore, cancer is growing in Saudi Arabia with 7,000 new cases being reported each year and the figure will reach 30,000 in 15 years, according to one expert [8]. The treatment of disseminated cancer has become increasingly aimed at molecular targets derived from studies of the oncogenes and tumor suppressors known to be involved in the development of human cancers [9]. This increase in specificity of cancer treatment, from the use of general cytotoxic agents such as nitrogen mustard in the 1940s, to the development of natural-product anticancer drugs in the 1960s such as Vinca alkaloids and anthracyclines, which are more cytotoxic to cancer cells than normal cells, to the use of specific monoclonal antibodies [10] and immunotoxins [11] targeted to cell surface receptors and specific agents that inactivate kinases in growth-promoting pathways [12], has improved the response rate in cancer and reduced side effects of anticancer treatment but has not yet resulted in cure of the majority of patients with metastatic disease. A study of the mechanisms by which cancers elude treatment has yielded a wealth of information about why these therapies fail and is beginning to yield valuable information about how to circumvent drug resistance in cancer cells and/or design agents that are not subject to the usual means of resistance.
The failure of the curative treatment of cancer patients often occurs as a result of intrinsic or acquired drug resistance of the tumor to chemotherapeutic agents. The resistance of tumors occurs not only to a single cytotoxic drug used, but also occurs as a cross-resistance to a whole range of drugs with different structures and cellular targets. This phenomenon is called multiple drug resistance (MDR). Once MDR appears, using high doses of drugs to overcome resistance is ineffective, toxic effects appear and resistance are further stimulated. Multidrug resistance (MDR) severely limits the effectiveness of chemotherapy in a variety of common malignancies and is responsible for the overall poor efficacy of cancer chemotherapy [13-17].
The cytotoxic drugs that are most frequently associated with MDR are hydrophobic, amphipathic natural products, such as the taxanes (paclitaxel and docetaxel), vinca alkaloids (vinorelbine, vincristine, and vinblastine), anthracyclines (doxorubicin, daunorubicin, and epirubicin), epipodophyllotoxins (etoposide and teniposide), antimetabolites (methorexate, fluorouracil, cytosar, 5-azacytosine, 6-mercaptopurine, and gemcitabine), topotecan, dactinomycin, and mitomycin C [16,18-20].
In spite of the large number of available chemotherapeutic agents the medical need is still largely unmet. The main reasons are: the lack of selectivity of conventional drugs, leading to toxicity; the metastatic spreading, implying early tumor implantation in organs other than primary site; the heterogeneity of the disease, comprising about 100 types of cancer; the intrinsic or acquired resistance to chemotherapy developed after few therapeutic cycles, i.e. multi-drug resistance (MDR) [21]. Therefore, new drugs that offer improvements over current therapies are desperately needed. New chemical entities with novel mechanisms of action will most likely possess activity against MDR cancer. [MDR severely limits the effectiveness of chemotherapy in a variety of common malignancies and is responsible for the overall poor efficacy of cancer chemotherapy [19-23].]